Phase 3 Efficacy and Safety Study of BG00012 in Pediatric Participants With Relapsing-Remitting Multiple Sclerosis (RRMS)

Biogen156 enrolled

Overview

The main objectives of Part 1 are as follows: To evaluate the safety, tolerability, and efficacy of BG00012 in pediatric participants with RRMS, as compared with a disease-modifying treatment and to assess health outcomes and evolution of disability. The primary objective of Part 2 is to evaluate the long-term safety of BG00012 in participants who completed Week 96 in Part 1 of Study 109MS306. The secondary objective of Part 2 is to describe the long-term MS outcomes of BG00012 in participants who completed Week 96 in Part 1 of Study 109MS306.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

156

Conditions

Relapsing-Remitting Multiple Sclerosis

Interventions

Eligibility

Sex: ALLMin age: 10 YearsMax age: 17 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: * Males and females aged from 10 to less than 18 years old at the time of informed consent or assent. * Must have a body weight of ≥30 kg. * Must have a diagnosis of RRMS (consensus definition for pediatric RRMS \[Krupp 2013\]). * Must be ambulatory with a baseline EDSS score between 0 and 5.5, inclusive. * Must have experienced at least 1 of the following 3 conditions: a) at least 1 relapse within the last 12 months prior to Day 1 with a prior brain MRI demonstrating lesions consistent with MS; b) at least 2 relapses within the last 24 months prior to Day 1, with a prior brain MRI demonstrating lesions consistent with MS; c) evidence of Gd-enhancing lesions of the brain on an MRI performed within the 6 weeks prior to Day 1. * Must be neurologically stable, with no evidence of relapse within 50 days prior to Day 1 and no evidence of corticosteroid treatment within 30 days prior to Day 1. * Participants of childbearing potential who are sexually active must be willing to practice effective contraception during the study and be willing and able to continue contraception for at least 30 days after their final dose of study treatment. Key Exclusion Criteria: * Primary progressive, secondary progressive, or progressive relapsing MS (as defined by \[Lublin and Reingold 1996\]). These conditions require the presence of continuous clinical disease worsening over a period of at least 3 months. Participants with these conditions may also have superimposed relapses but are distinguished from relapsing-remitting participants by the lack of clinically stable periods or clinical improvement. * Disorders mimicking MS, such as other demyelinating disorders (e.g., acute disseminated encephalomyelitis), systemic autoimmune disorders (e.g., Sjögren disease, lupus erythematosus), metabolic disorders (e.g., dystrophies), and infectious disorders. * History of premalignant or malignant disease. Participants with basal cell carcinoma that has been completely excised prior to screening will remain eligible. * History of severe allergic or anaphylactic reactions, or known drug hypersensitivity to DMF, fumaric acid esters, or interferon beta-1a (IFN Beta-1a). * History of abnormal laboratory results indicative of any significant endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, renal, and/or any other major disease that would preclude participation in a clinical study. * History of clinically significant cardiovascular, pulmonary, GI, dermatologic, growth, developmental, psychiatric (including depression), neurologic (other than MS), and/or other major disease that would preclude participation in a clinical study. * History of human immunodeficiency virus. * An MS relapse that has occurred within 50 days prior to Day 1 AND/OR the participant has not stabilized from a previous relapse prior to Day 1. * Other unspecified reasons that, in the opinion of the Investigator or Biogen Idec, make the participant unsuitable for enrollment. NOTE: Other protocol-defined inclusion/exclusion criteria may apply

Locations (62)

Boston Children's Hospital

Boston, Massachusetts, United States

The Rector and Visitors of the University of Virginia

Charlottesville, Virginia, United States

Universitair Kinderziekenhuis Koningin Fabiola

Brussels, Belgium

Universitair Ziekenhuis Ghent

Ghent, Belgium

MHATNP 'Sv.Naum', EAD

Sofia, Bulgaria

Outcomes

Primary Outcomes

Part 1: Proportion of Participants Free of New or Newly Enlarging T2 Hyperintense Lesions on Brain Magnetic Resonance Imaging (MRI) Scans

Participants who were free of new or newly enlarging T2 hyperintense lesions were assessed on Brain MRI scans.

Time frame: At Week 96

Part 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

An adverse event (AE) was any unfavorable and unintended sign (including an abnormal assessment such as an abnormal laboratory value), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. An SAE was any untoward medical occurrence that at any dose resulted in death, in the view of the Investigator, placed the participant at immediate risk of death, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in a birth defect. TEAEs were defined as AEs occurring or worsening after beginning study treatment (after the first dose).

Time frame: From Week 96 up to last follow-up visit (up to Week 340)

Part 2: Number of Participants Who Discontinued Study Treatment Due to an AE

Time frame: From Week 96 up to last follow-up visit (up to Week 340)

Secondary Outcomes

Part 1: Number of New or Newly Enlarged T2 Hyperintense Lesions on Brain MRI Scans

The number of new or newly enlarging T2 hyperintense lesions that developed in each participant was assessed on Brain MRI scans.

Time frame: At Weeks 24 and Week 96

Part 1: Proportion of Participants Free of New or Newly Enlarging T2 Hyperintense Lesions on Brain MRI Scans

Participants who were free of new or newly enlarging T2 hyperintense lesions were assessed on Brain MRI scans.

Time frame: At Weeks 24 and 48

Part 1: Proportion of Participants Free of New MRI Activity as Measured by Brain MRI Scans

Participants free of Gd-enhancing MRI lesions and new or newly enlarging T2 MRI lesions were assessed on Brain MRI Scans.

Time frame: At Weeks 24, 48, and 96

Part 1: Time to First Relapse

Relapses are defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the examining neurologist. The time to first relapse was defined as the time from the first dose in Part 1 up to the first relapse. Time to First Relapse was estimated by Kaplan-Meier method.

Time frame: Up to Week 96

Part 1: Proportion of Relapse-Free Participants

Relapses are defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the examining neurologist. The proportion of relapse-free participants was estimated using the Kaplan-Meier method.

Time frame: Up to Week 96

Part 1: Annualized Relapse Rate (ARR)

ARR is calculated as the total number of relapses that occurred during the study divided by the total number of participant-years. ARR was analyzed using negative binomial regression model.

Time frame: At Weeks 48 and 96

Part 1: Number of Participants With TEAEs and TESAEs

An AE was any unfavorable and unintended sign (including an abnormal assessment such as an abnormal laboratory value), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. An SAE was any untoward medical occurrence that at any dose resulted in death, in the view of the Investigator, placed the participant at immediate risk of death, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in a birth defect. TEAEs were defined as AEs occurring or worsening after beginning study treatment (after the first dose).

Time frame: From Day 1 up to Week 96

Part 1: Change From Baseline in Vital Signs (Temperature)

Negative change from baseline indicated reduction in temperature.

Time frame: Baseline, Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84 and 96

Part 1: Change From Baseline in Vital Signs (Pulse Rate)

Negative change from baseline indicated reduction in pulse rate.

Time frame: Baseline, Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84 and 96

Part 1: Change From Baseline in Vital Signs (Blood Pressure)

Negative change from baseline indicated reduction in blood pressure.

Time frame: Baseline, Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84 and 96

Part 1: Change From Baseline in Vital Signs (Respiratory Rate)

Negative change from baseline indicated reduction in respiratory rate.

Time frame: Baseline, Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84 and 96

Part 1: Number of Participants With Shifts From Baseline in Electrocardiograms (ECG) Abnormalities

Clinical significance of abnormalities in ECG was determined based on the investigator's discretion. Shift to abnormal indicated values that were normal or unknown at baseline and shifted to abnormal values post-baseline.

Time frame: Up to Week 96

Part 1: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters)

Hematology parameters included leukocytes, erythrocytes, hemoglobin, hematocrit, platelets, eosinophils, lymphocytes, monocytes and neutrophils. These parameters were flagged as low, normal, or high relative to parameter's normal range or as unknown if no result was available. Here, shift to low indicated values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicated values that were normal, low or unknown at baseline and shifted to high postbaseline values. The categories with at least one participant with shift from baseline in these parameters are reported.

Time frame: Baseline up to Week 96

Part 1: Change From Baseline in Coagulation Parameters [Activated Partial Thromboplastin Time (aPTT)]

A negative change from baseline indicated a reduction in aPTT.

Time frame: Baseline, Weeks 24, 48 and 96

Part 1: Change From Baseline in Coagulation Parameters [Prothrombin Time (PT)]

A negative change from baseline indicated a reduction in PT.

Time frame: Baseline, Weeks 24, 48 and 96

Part 1: Change From Baseline in Coagulation Parameters [International Normalized Ratio (INR)]

A negative change from baseline indicated a reduction in clotting time.

Time frame: Baseline, Weeks 24, 48 and 96

Part 1: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters)

Parameters included sodium, potassium, chloride, bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, urea nitrogen, creatinine, bicarbonate, calcium, magnesium, phosphate, urate and glucose. These parameters were flagged as low, normal or high relative to parameter's normal range or as unknown if no result was available, by Investigator. Here, shift to low indicated values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicated values that were normal, low or unknown at baseline and shifted to high values postbaseline. Categories with at least one participant with shift from baseline in these parameters are reported.

Time frame: Baseline up to Week 96

Part 1: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters)

Urinalysis included assessments of glucose, ketones, occult blood, protein, specific gravity. These parameters were flagged as low, normal, or high relative to parameter's normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicated values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicated values that were normal, low or unknown at baseline and shifted to high postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported.

Time frame: Baseline up to Week 96

Part 1: Fatigue Score Measured by the Pediatric Quality of Life Inventory (PedsQL) Multidimensional Fatigue Scale

The PedsQL multidimensional fatigue questionnaire was answered by the participant (self-assessment) and parent. The fatigue scale contains 18 questions in 3 fatigue dimensions: general fatigue, sleep/rest fatigue and cognitive fatigue. Each item was scored on 5-point Likert scale (0=never to 4=almost always). Each individual score was then reversed (subtracted from 4) and linearly transformed as follows: 0=100, 1=75, 2=50, 3=25, 4=0. For each dimension, total score was calculated as the sum of all the items/number of items answered. A higher total score indicated fewer problems.

Time frame: Up to Week 96

Part 1: Quality of Life (QOL) as Measured by the PedsQL

The PedsQL QOL questionnaire was answered by the participant (self-assessment) and parent. The QoL scale contains 23 questions in 4 dimensions: Physical Functioning, Emotional Fatigue, Social Fatigue and School Fatigue. Each item was scored on 5-point Likert scale (0=never to 4=almost always). Each individual score was then reversed (subtracted from 4) and linearly transformed as follows: 0=100, 1=75, 2=50, 3=25, 4=0. For each dimension, total score was calculated as the sum of all the items/number of items answered. A higher total score indicated better quality of life.

Time frame: Up to Week 96

Part 1: Change From Baseline in the Expanded Disability Status Scale (EDSS) Score

The EDSS measures the disability status of participants with multiple sclerosis on a scale that ranges from 0 to 10. The first levels 1.0 to 4.5 refer to people with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 refer to the loss of ambulatory ability. The range of main categories include (0) = normal neurologic exam; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to MS with higher scores indicating more disability. A negative change from baseline indicated an improvement in the disability.

Time frame: Baseline, Week 96

Part 2: Annualized Relapse Rate (ARR)

ARR is calculated as the total number of relapses that occurred during the study divided by the total number of participant-years. ARR was analyzed using negative binomial regression model.

Time frame: From Baseline (Week 96) up to Week 336

Part 2: Change From Baseline in the Expanded Disability Status Scale (EDSS) Score

The EDSS measures the disability status of participants with multiple sclerosis on a scale that ranges from 0 to 10. The first levels 1.0 to 4.5 refer to people with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 refer to the loss of ambulatory ability. The range of main categories include (0) = normal neurologic exam; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to MS. A negative change from baseline indicated an improvement in the disability.

Time frame: Baseline (Week 96), Week 336

Part 2: Change From Baseline in Brief Visuospatial Memory Test - Revised (BVMT-R) Score

BVMT-R is used to assess learning/memory. In this test, six abstract designs are presented for 10 sec. The display is removed from view, and participants render the stimuli via pencil on paper, manual responses. Each design receives from 0 to 2 points, representing accuracy and location. There are three Learning Trials, and the score is reported as the total number of points earned over the trials. Thus, scores range from 0 to 12 per trial; total score range is 0 to 36 for all three trials. Scores were converted to standardized scores using normative data, ranging from 2-86. The lower the score, the more severe the cognitive impairment while higher scores reflect better visuospatial memory.

Time frame: Baseline (Week 96), Weeks 144,192, 240, 288 and 336

Part 2: Change From Baseline in Symbol Digit Modalities Test (SDMT) Score

SDMT is used to assess processing speed. It consists of 9 abstract symbols. Each symbol is paired with a single digit. The participant is provided with a key, showing each symbol digit pair. In addition, the participants are shown several rows of the 9 symbols, which are arranged pseudo-randomly, without the digit. Participants are asked to voice the digit associated with each symbol as rapidly as possible for 90 seconds. The SDMT score ranges from 0 to 110, where higher scores indicate improvement in cognitive functioning and lower scores indicate worsening.

Time frame: Baseline (Week 96), Weeks 144,192, 240, 288 and 336

Part 2: Number of Participants With or Without School Progression

Participants or caregivers were posed the following question: "During the past year, did \[you/the participant\] progress from one \[class/grade-level\] to the next in school?" Responses were recorded as Yes (participant advanced to the next grade) or No (participant did not advance).

Time frame: At Weeks 144, 192, 240, 288 and 336

Part 2: Change From Baseline in Vital Signs (Temperature)

Negative change from baseline indicated reduction in temperature.

Time frame: Baseline (Week 96), Weeks 120,144, 168, 192, 216, 240, 264, 288, 312, 336, and 340

Part 2: Change From Baseline in Vital Signs (Pulse Rate)

Negative change from baseline indicated reduction in pulse rate.

Time frame: Baseline (Week 96), Weeks 120,144, 168, 192, 216, 240, 264, 288, 312, 336, and 340

Part 2: Change From Baseline in Vital Signs (Blood Pressure)

Negative change from baseline indicated reduction in blood pressure.

Time frame: Baseline (Week 96), Weeks 120,144, 168, 192, 216, 240, 264, 288, 312, 336, and 340

Part 2: Change From Baseline in Vital Signs (Respiratory Rate)

Negative change from baseline indicated reduction in respiratory rate.

Time frame: Baseline (Week 96), Weeks 120,144, 168, 192, 216, 240, 264, 288, 312, 336, and 340

Part 2: Number of Participants With Shifts From Baseline in ECG Abnormalities

Time frame: From Baseline (Week 96) to Week 336

Part 2: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters)

Time frame: Baseline (Week 96) up to Week 340

Part 2: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters)

Parameters included potassium, bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, urea nitrogen, creatinine, bicarbonate, calcium, magnesium, phosphate, urate and glucose. These parameters were flagged as low, normal or high relative to parameter's normal range or as unknown if no result was available, by Investigator. Here, shift to low indicated values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicated values that were normal, low or unknown at baseline and shifted to high values postbaseline. Categories with at least one participant with shift from baseline in these parameters are reported.

Time frame: Baseline (Week 96) up to Week 340

Part 2: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters)

Urinalysis included assessments of erythrocytes, leukocytes and specific gravity. These parameters were flagged as low, normal, or high relative to parameter's normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicated values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicated values that were normal, low or unknown at baseline and shifted to high postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported.

Time frame: Baseline up to Week 340

Part 2: Change From Baseline in Height

Time frame: Baseline (Week 96), Weeks 120,144, 168, 192, 216, 240, 264, 288, 312, 336, and 340

Part 2: Change From Baseline in Weight

Time frame: Baseline (Week 96), Weeks 120,144, 168, 192, 216, 240, 264, 288, 312, 336, and 340

Part 2: Change From Baseline in Bone Age

Bone age was tested until the participant reached a bone age of 16 years.

Time frame: Baseline (Week 96), Weeks 144, 192 and 240

Part 2: Number of Male Participants by Tanner Stage Assessment

Tanner pubertal staging in males was assessed for testes and scrotum development and pubic hair growth, progressing from stage 1 (prepubertal) to stage 5 (adult). Assessments ended when bone age reached ≥16 years. Testes and scrotum stages were: 1-prepubertal; 2-enlargement of testes, scrotum reddens, texture change; 3-Enlargement of penis, further growth of testes; 4-Increased size of penis with growth in breadth and development of glans; testes and scrotum larger, scrotum skin darker; 5-adult genitalia. Pubic hair stages were: 1-prepubertal; 2-Sparse growth of long, slightly pigmented hair, straight or curled; 3-Darker, coarser and more curled hair, spreading sparsely over junction of pubes; 4-Hair adult in type, but covering smaller area than in adult; no spread to medial surface of thighs; 5-Adult in type and quantity, with horizontal distribution.

Time frame: At Weeks 96, 144, 192, 240, 288 and 336

Part 2: Number of Female Participants by Tanner Stage Assessment

Tanner pubertal staging in females was assessed for breast development and pubic hair growth, progressing from stage 1 (prepubertal) to stage 5 (adult). Assessments ended when bone age reached ≥16 years or the participant was post-menarche. Breast development stages: 1-prepubertal; 2-breast bud stage with elevation of breast and papilla; enlargement of areola, 3-further enlargement of breast and areola; no separation of their contour; 4-areola and papilla form secondary mound above level of breast; 5-mature stage: projection of papilla only, related to recession of areola. Pubic hair stages: 1-prepubertal (can see velus hair similar to abdominal wall); 2-sparse growth of long, slightly pigmented hair, straight or curled, mainly on labia; 3-Darker, coarser and more curled hair, spreading sparsely over junction of pubes; 4-hair adult in type, but covering smaller area than in adult; no spread to medial surface of thighs; 5-adult in type and quantity, with horizontal distribution.

Time frame: At Weeks 96, 144, 192, 240, 288 and 336